Abstract Lung cancer remains a leading cause of cancer-related deaths in the United States with unfavorable prognosis mainly due to tumor relapse and metastasis, which are recently believed to be caused by a specific population of cancer cells within tumor termed “cancer stem cells (CSCs)”. These cells share the common characteristic of self-renewal and differentiation as normal stem cell, but also show resistance to chemotherapy and radiation therapy. Thus, targeting CSC populations in lung tumors is critical to the prevention of tumor metastasis. Xeroderma pigmentosum group C (XPC) was first recognized as a DNA repair protein. As a DNA repair factor, XPC plays an important role in preventing carcinogenesis. However, it has also been reported that XPC insufficiency is associated with poor treatment outcomes for a variety of cancers, and low expression of XPC is correlated with poor prognosis of lung cancer patients, suggesting that XPC may suppress lung cancer progression. Here, we show that downregulation of XPC expanded lung CSCs characterized by CD133+, while overexpression of XPC limited this cell population, as well as reduced the tumorigenic potential of the lung cancer cell line. Furthermore, we found that XPC knockdown is able to promote the CD133--to-CD133+ cell conversion in A549 cells, indicating that XPC can inhibit lung cancer cell dedifferentiation. Mechanistic investigation demonstrated that XPC can suppress Snail expression by directly binding to the promoter region of the SNAI1 gene, leading to the enrichment of histone H3 trimethylation at serine 27 (H3K27me3) and loss of histone H3 acetylation at serine 27 (H3K27Ac) in this region. Given that Snail plays a critical role in the induction of epithelial-mesenchymal transition (EMT), which is a major mechanism for the acquisition of stem cell-like properties, we believe that XPC can limit the CSC population by inhibiting cancer cell dedifferentiation. In summary, we conclude that low expression of XPC in lung tumors can de-repress the expression of Snail, promote EMT, and increase the de novo production of CSCs, eventually facilitating lung tumor progression. Citation Format: Shurui Cai, Dayong Wu, Ananya Banerjee, Lu Liu, Chunhua Han, Tiantian Cui, Qi-En Wang. XPC inhibits lung cancer cell dedifferentiation by suppressing Snail expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3691.